Retinoblastoma is a childhood cancer of the developing retina that begins in utero and is diagnosed in the first years of life. It is the third most common form of cancer in infants after leukemia and neuroblastoma. If left untreated, retinoblastoma is virtually always fatal, and even with the best treatment, the 10% survival rate for metastatic retinoblastoma is among the worst for any pediatric cancer. In the U.S., most patients survive because the cancer is detected early before it metastasizes, but saving the patient's life often requires surgical enucleation. This is particularly debilitating for children ith the most advanced form of bilateral retinoblastoma; approximately half of those patients lose at least 1 eye and are permanently vision impaired. The goal of this translational research is to identify new treatments to save the vision of children with retinoblastoma and the lives of children with metastatic progression. We have identified 3 novel, exciting molecular-targeted therapies that show promise in laboratory studies. In this application, we will perform comprehensive preclinical testing of these 3 agents. The results from these studies will be used to design the next retinoblastoma clinical trial at St. Jude Children's Research Hospital. Therefore, the successful completion of the Aims presented here will directly impact human health. One unique and innovative aspect of this application is the multidisciplinary team that we have assembled, which is made up of ocular oncologists, pediatric oncologists, developmental neurobiologists, chemists, and pharmacologists. This team has a proven record of moving basic science discoveries into clinical trials and then sharing our findings with the national and international communities to affect the greatest change in global human health. Another innovative aspect of the application is our expertise in retinoblastoma translational research and development of preclinical models, which we have optimized and characterized for these studies. No other center has the team, resources, expertise, or tools available to perform the studies presented here and move the most promising findings directly into a clinical trial.